The role of intestinal microbiota and its metabolites in metabolic diseases

Background

The global prevalence of metabolic diseases such as obesity, non-alcoholic fatty liver disease (NAFLD), insulin resistance, type 2 diabetes mellitus (T2DM), atherosclerosis (AS) and polycystic ovary syndrome (PCOS) has increased dramatically . Over the past few decades, the consumption of high-calorie foods has increased and physical activity has been replaced by sedentary activities, ultimately resulting in energy intake exceeding energy expenditure and becoming a major risk factor for obesity and obesity-related diseases. In this condition, adipose tissue exceeds the body's ability to store all excess energy in the form of triglycerides, causing lipids to overflow into the circulation. This excess recruitment of lipids in non-disaccharide tissues results in ectopic fat storage, in which the ability of non-adipose tissue to increase fat oxidation upon increased fatty acid utilization is impaired. Excessive accumulation of fat in adipocytes can trigger increased production and secretion of pro-inflammatory adipokine, leading to the occurrence of insulin resistance, which is related to the occurrence of T2DM and NAFLD. Genetically speaking, more than 99% of human genes are microorganisms, and there are at least as many microbial cells as there are human body cells. The gut microbiota refers to the trillions of microorganisms residing in the gut, including bacteria, viruses, fungi, archaea, phages, and protozoa, which can interact with the host in a variety of ways.

 

 

Introduction

 

Professor Changtao Jiang and his team from Peking University Third Hospital published a review titled The role of the gut microbiome and its metabolites in metabolic diseases [1] in the journal Protein Cell (IF: 10.164), focusing on the intestinal microbiota. and the role of their metabolites in the onset and progression of many metabolic diseases, as well as the underlying mechanisms and new technologies for creating a range of various target-specific drugs for treatment. This review aims to provide guidance for future research in the emerging field of gut microbiota relevant to the development of metabolic diseases in humans.

 

Main results

Correlation between gut microbiota and metabolic diseases

The potential role of the gut microbiota in the development of various diseases in humans has received considerable attention over the past decade. In particular, the gut microbiota has evolved to become an important factor in the development of many metabolic diseases, such as obesity, type 2 diabetes, and non-alcoholic fatty liver disease. We summarize changes in gut microbiota composition in metabolic diseases. The current global obesity epidemic is associated with lifestyle changes characterized by excessive energy intake and reduced physical activity. Western diet-induced obesity leads to changes in the composition of the gut microbiota, such as a significant increase in Firmicutes. As a potential mechanistic driver of obesity and its related comorbidities, the impact of intestinal microbiota has become a focus of attention in recent years. The gut microbiota is key to energy acquisition as it converts food into nutrients for the host, and obesity-associated gut microbiota are more capable of harvesting energy from the diet. Previous studies have shown that intestinal microbiota has an important impact on the occurrence and development of non-alcoholic fatty liver disease in humans. The abundance of Bacteroidetes was increased in patients with non-alcoholic fatty liver disease, while the abundance of short-chain fatty acid-producing and 7α-dehydroxyfirmicutes was significantly decreased. A study using a transplanted mouse model demonstrates the role of the gut microbiota in the development of non-alcoholic fatty liver disease. Mice fed a high-fat diet developed hepatic macrovesicular steatosis after colonization with microbiota from hyperglycemic mice, whereas control mice developed only low-level steatosis after treatment with microbiota from normoglycemic mice. . Differences in microbiota composition can determine how mice respond to HFD disease. In summary, the intestinal microbiota has a significant impact on systemic metabolic homeostasis, and a healthy intestinal microbiota plays an important role in the overall health of the host.

 

 

Major metabolites produced in the gut microbiota

The human gut microbiota is driven by macronutrients in the diet and produces bioactive compounds composed of bile acids, short-chain fatty acids, ammonia, phenols, endotoxins, and more. These microbiota-derived metabolites act as mediators of microbe-host communication, which is essential for maintaining host physiology.

 

 

Bile acid

Primary bile acids are converted from cholesterol to taurine and glycine conjugates in the liver and secreted into the intestine where they are converted to secondary bile acids in the intestinal microbiota by bile salt hydrolase (BSH). Bile acids alter metabolism by activating certain receptors, including farnesoid X receptors (FXR), pregnane X receptors, and G protein-coupled receptors (GPCRs), such as TGR5. The secondary bile acids deoxycholic acid (DCA) and lithocholic acid (LCA) are the most abundant metabolites in the intestinal microbiota, accumulating at a concentration of approximately 500 μmol/L and regulating the host through the G protein-coupled receptor TGR5 Energy homeostasis and metabolism. Intestinal FXR activation induces hepatic fibroblast growth factor 15 (FGF15) expression and inhibits cholesterol 7α-hydroxylase (CYP7A1) expression. CYP7A1 is the rate-limiting step in bile acid synthesis and thus can lead to decreased bile acid levels through the gut-microbiota-liver feedback pathway.

Modulation of the gut microbiota-bile acid-FXR axis is associated with obesity-induced insulin resistance and hepatic steatosis in mice. Figure 1 summarizes the previous related work of our laboratory, revealing that regulating CYP7A1, a key enzyme in the bile acid synthesis pathway of hamsters, eliminates intestinal microbiota to reduce HFD-induced glucose intolerance, hepatic steatosis, and inflammation. Provides potential targets for modulating diet-induced obesity.

 

 

The regulatory role of bile acids

The intestinal microbiota is critical for maintaining the host's physiological state and metabolic homeostasis. The intestinal flora of patients with metabolic diseases is dysbiosis, and the interaction between the intestinal flora and the host is disordered. Therefore, modulating the host gut microbiota may be a promising therapeutic approach to treat metabolic diseases. Gut microbiota colonization is thought to begin primarily at birth, when the infant is exposed to maternal microbiota during delivery. Multiple factors early in life influence the composition of the gut microbiota, including mode of delivery, host genetics, immune response, antibiotic administration, lifestyle, circadian rhythms, host disease status, and environment.

 

 

Effects of dietary intervention on gut microbiota and bile acid composition

Throughout a person's life, diet may have the greatest impact on the relationship between the gut microbiota and its mammalian host. The consumption of various nutrients affects the structure of the microbiota and provides substrates for microbial metabolism. The gut microbiota interacts with nutrients in food to influence host health. Furthermore, the structure and activity of the gut microbiota are largely regulated by human dietary intake, and this process is rapid and reproducible. Therefore, dietary intervention is a powerful tool to alter the composition of the gut microbiota. There were significant differences in gut microbiota composition between herbivorous and carnivorous individuals, with a carnivorous diet increasing the abundance of bile-tolerant microorganisms and reducing levels of Firmicutes that metabolize dietary plant polysaccharides, such as Roseberia , rectal eubacteria and Ruminococcus brucei, etc.

 

 

Gut-targeted drugs to treat metabolic diseases

In addition to dietary intervention, drugs are the main intervention strategy for metabolic diseases. The gut microbiota is widely recognized as a major regulator of host health and a driver of changes in microbial composition and function, with important impacts on host health. The gut microbiota interacts with several common antidiabetic drugs, including metformin, thiazolidinediones, miglitol, acarbose, and liraglutide, among others.

 

 

Probiotic administration

Currently, probiotic treatment is commonly used to prevent metabolic diseases such as diabetes and non-alcoholic fatty liver disease. In order to study the effects of probiotics on the host, it is crucial to assess whether probiotics colonize the intestine. A recent systematic review reported that six out of seven analyzed studies found no effect of probiotics on fecal microbiota composition. In contrast, other studies have observed changes in fecal microbiota composition in probiotic-treated individuals.

 

 

Gene editing technology for gut microbiota

In addition to the dietary interventions and probiotics mentioned above, there are other ways to modulate the composition of the gut microbiota. A recent publication by Stanford University researchers developed a system for constructing a complete knockout of Clostridium difficile and determined the function of the microbial product. Clostridium is a commensal bacterium of the phylum Firmicutes that is commonly found in the gut of mammals. Clostridia produce a range of metabolites that diffuse into the host circulation and are genetically difficult to manipulate. To study the role of molecules produced by the gut microbiota, Guo et al. developed a CRISPR-Cas9-based genetic system to create deletions in model Clostridium commensalis that stop the production of specific molecules.

 

 

Conclusion and outlook

Our guts are home to a vast array of microorganisms, from bacteria, viruses, fungi and archaea to bacteriophages and protozoa. The intestinal microbiota can regulate nutrient metabolism during dietary intake and produce many metabolites that interact with the host in various ways, including regulating glucose and lipid metabolism pathways, affecting the differentiation and function of immune cells, affecting insulin sensitivity, etc. Extensive human and animal data provide strong evidence that the gut microbiota and its metabolites play a crucial role in the onset and progression of many metabolic diseases. Based on recent research and experimental results, we have discovered many ways to improve metabolic diseases by modulating the gut microbiota, including dietary intervention, probiotic administration, gene editing technology, and drug use. In addition to the applications mentioned above, we can also predict a person's susceptibility to disease or response to drugs by detecting characteristics of a person's microbiome.

According to many clinical follow-up studies from different countries, the majority of individuals (perhaps up to 70% with a prediabetic state, including impaired fasting glucose (IFG) and impaired glucose tolerance (IGT)) may eventually develop type 2 diabetes. Furthermore, prediabetes is strongly associated with other manifestations, including obesity, hypertension, nonalcoholic fatty liver disease, hypertriglyceridemia, and cardiovascular disease. A 2015 cohort study continuously monitored the blood sugar levels of 800 subjects for a week and collected data on their microbiome, genetics, eating habits, anthropometry and physical activity. The researchers demonstrated that people respond differently to the same meal and designed a machine learning algorithm to use individual and microbiota characteristics to accurately predict glucose responses.

There is no doubt that we have made great progress in the composition of the gut microbiota and the analysis of key metabolites. However, we need to do more than simple correlation. The complex mechanisms of interactions between the gut microbiota and the host await further investigation.